Investigators: Catherine Lemière1, John Brannan2, Sandra D. Anderson3 and Jean-Luc Malo1
Student: David Miedinger, post-doctoral fellow; 1Center for Asthma at the Workplace, Hôpital du Sacré-Coeur, Montréal, QC, Canada; Firestone Institute for Respiratory Health, Hamilton, ON, Canada; 3Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
Introduction: Bronchial hyperresponsiveness (BHR) is a hallmark of asthma that can be assessed by performing bronchial provocation tests (BPTs) using direct (methacholine, histamine) or indirect stimuli (exercise, hypertonic saline, adenosine-monophosphate and mannitol). Mannitol BPT seems more correlated with airway inflammation than methacholine challenge. Bronchial hyperreactivity seems to persist longer than airway inflammation in subjects with occupational asthma (OA) after removal from exposure. Whether airway reactivity as measured by methacholine persist longer than airway reactivity measured by mannitol in subjects with OA removed from exposure remains to determine. Mannitol has an osmotic effect causing water efflux in the airway lumen (1). Therefore, mannitol might be an alternative substance to hypertonic saline to induce effectively sputum in patients with OA. This method may allow assessing bronchial reactivity and inducing sputum concomitantly, which will represent a substantial gain in time.
Aims: 1.To compare the persistence of bronchial reactivity assessed by methacholine and by mannitol in subjects with OA 5 years after removal from exposure. 2. To compare the yield and quality of sputum produced after a challenge test with mannitol and after inhalation of hypertonic saline following a methacholine challenge. 3. To assess the correlatation between bronchial reactivity assessed by mannitol with sputum eosinophil count and exhaled nitric oxide (NO)
Methods: Cross-sectional study comparing bronchial reactivity as measured by methacholine challenge and mannitol challenge in subjects with OA removed from exposure for at least 5 years. Subjects who had OA diagnosed in our center by specific inhalation challenge between 2000 and 2005 will be invited to participate in our study. The measurement of exhaled nitric oxide will be done according to current guidelines (2) with a portable analysing device (NioxMINO, Aerocrine, Solna, Sweden). Methacholine challenge will be performed as previously described and sputum will be induced after methacholine challenge following our usual procedure (3). Subjects will undergo mannitol challenge testing within 7 days after the methacholine challenge and at least 48h hours after this test. Mannitol test will be performed according to the standardized protocol (4). Sputum will be collected during and after the mannitol test. In subjects with a positive test (fall of FEV1 15% from baseline) we will administer 400 mcgs of salbutamol, wait until the FEV1 is back within 10% of the baseline and then continue the challenge test until the maximum dose of 635mg of mannitol is administered. During this period of time sputum will be collected. In subjects without a fall of FEV1 ≥15% from baseline and in whom the total dose of 635mg of mannitol was administered, we will wait for spontaneous recovery of their lung function and ask the subjects to produce sputum during this time. If subjects do not produce a sample of good quality we will stop after 15 minutes. Sputum collected during the mannitol test and after inhalation of hypertonic saline will be processed and analyzed according to a standardized protocol (3).
In this pilot study we intend to investigate 40 subjects. 1) We will compare the proportion of subjects with and without reactivity to methacholine or mannitol by using chisquare or Fishers exact test. 2) We will compare the proportion of successful sputum induction as well as salivary contamination of the sample after mannitol test with the results obtained after hypertonic saline induction by using chi-square or Fishers exact test. 3) We will calculate the correlation of dose response ratios to methacholine with sputum eosinophil counts and levels of exhaled nitric oxide by calculating spearman’s correlation coefficients.
Significance: If mannitol BPT is more closely correlated with airway inflammation and respiratory symptoms than methacholine challenge mannitol BPT will need to be further evaluated as a potential alternative for the current used standard of BPT in the evaluation for permanent disability in subjects with OA. If sputum induction with mannitol yields the same proportion of good quality sputum samples than with hypertonic saline, this method might be a time saving and cheap alternative that would have the potential to be used in the field (workplace) by experienced personnel after conducting BPT with mannitol.
Budget: The budget requested ($20.000) will cover costs of a research assistant for recruitment and data collection, study materials and compensation offered to participants.
References: 1) Daviskas E, Respirology 2007. 2) Official statement of the American Thoracic Society, Am J Respir Crit Care Med 1999. 3) Pin I, Thorax 1992 4) Anderson SD, Am J Respir Crit Care Med 1997